Nanoparticle-based therapeutic delivery of prohibitin to the colonic epithelial cells ameliorates acute murine colitis

Inflamm Bowel Dis. 2011 May;17(5):1163-76. doi: 10.1002/ibd.21469. Epub 2010 Sep 24.

Abstract

Background: Intestinal epithelial expression of antioxidants and nuclear factor kappa B (NF-κB) contribute to mucosal barrier integrity and epithelial homeostasis, two key events in the pathogenesis of inflammatory bowel disease (IBD). Genetic restoration of intestinal epithelial prohibitin 1 (PHB) levels during experimental colitis reduces the severity of disease through sustained epithelial antioxidant expression and reduced NF-κB activation. To determine the therapeutic potential of restoring epithelial PHB during experimental colitis in mice, we assessed two methods of PHB colonic mucosal delivery: adenovirus-directed administration by enema and poly(lactic acid) nanoparticle (NPs) delivery by gavage.

Methods: As a proof-of-principle to demonstrate the therapeutic efficacy of PHB, we utilized adenovirus-directed administration by enema. Second, we used NPs-based colonic delivery of biologically active PHB to demonstrate therapeutic use for human IBD. Colitis was induced by oral administration of dextran sodium sulfate (DSS) in water for 6-7 days. Wildtype mice receiving normal tap water served as controls.

Results: Both methods of delivery resulted in increased levels of PHB in the surface epithelial cells of the colon and reduced severity of DSS-induced colitis in mice as measured by body weight loss, clinical score, myeloperoxidase activity, proinflammatory cytokine expression, histological score, and protein carbonyl content.

Conclusions: This is the first study to show oral delivery of a biologically active protein by NPs encapsulated in hydrogel to the colon. Here we show that therapeutic delivery of PHB to the colon reduces the severity of DSS-induced colitis in mice. PHB may represent a novel therapeutic target in IBD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Caco-2 Cells
  • Colitis / drug therapy*
  • Colitis / metabolism
  • Colitis / pathology
  • Disease Models, Animal
  • Drug Delivery Systems / methods*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NF-kappa B / metabolism
  • Nanoparticles / therapeutic use*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacokinetics
  • Repressor Proteins / genetics*
  • Repressor Proteins / pharmacokinetics*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • NF-kappa B
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Tumor Necrosis Factor-alpha
  • prohibitin
  • Green Fluorescent Proteins